One of the most common observations in cell death assays is that not all cells die at the same time, or at the same treatment dose. Here, using the perspective of the systems biology of apoptosis and the context of cancer treatment, we discuss possible sources of this cell-to-cell variability as well as its implications for quantitative measurements and computational models of cell death. Many different factors, both within and outside of the apoptosis signaling networks, have been correlated with the variable responses to various death-inducing treatments. Systems biology models offer us the opportunity to take a more synoptic view of the cell death process to identify multifactorial determinants of the cell death decision. Finally, with an eye toward ‘systems pharmacology', we discuss how leveraging this new understanding should help us develop combination treatment strategies to compel cancer cells toward apoptosis by manipulating either the biochemical state of cancer cells or the dynamics of signal transduction.